Smoking has long been recognized as the primary risk factor for development of COPD, but factors that determine which smokers will develop significant disease are largely unknown. Recent interest has focused on the potential role of infectious agents and the associated host response in accelerating progression of airway obstruction or in perpetuating its progression following discontinuation of tobacco exposure. Several lines of data generated from our group's human and primate studies strongly suggest that Pneumocystis (Pc) colonization is an important co-factor in development or progression of COPD in certain individuals. Pc in the lungs produces inflammatory changes similar to those seen in COPD. Colonization is increased in smokers and is independently associated with COPD severity. HIV-infected subjects who are Pc-colonized have significantly greater airway obstruction than non-colonized controls. In non-human primates, Pc colonization results in airway obstruction and radiographic emphysema. The emerging heterogeneity of COPD phenotypes (i.e. airway obstruction, parenchymal destruction, small airway disease) suggests that different etiologic factors might be important in different patients. Currently, we are unable to identify particular COPD phenotypes associated with Pc colonization and understanding of the mechanism by which colonization worsens COPD is limited. We hypothesize that Pc colonization results in particular physiologic and genomic phenotypes of COPD and that colonization stimulates BALT formation in susceptible smokers. We will test these hypotheses in the diverse phenotypes of COPD available from the Lung Tissue Research Consortium (LTRC) subjects by performing the following specific aims: 1) To identify the specific clinical, physiologic, and radiographic phenotypes associated with Pc colonization in subjects with COPD, 2) To test the hypothesis that specific anatomic phenotypes are associated with Pc colonization, 3) To test the hypothesis that Pc colonization results in specific gene expression patterns. This proposal represents a major step in determining the role of Pc in COPD and in elucidating the mechanism by which it results in disease. It will take advantage of the existing COPD-focused collaborations at the University of Pittsburgh and maximize use of the resources provided by the LTRC. This work has the potential to improve understanding of the role and mechanism of Pc colonization in COPD and to identify patients who might ultimately benefit from treatment of Pc. (End of Reviewer's Comments) PUBLIC HEALTH RELEVANCE: The reasons why some smokers develop chronic obstructive pulmonary disease (COPD) and others do not are not understood. We believe that infections with an organism called Pneumocystis might cause some cases of COPD, and we will try to determine which people with COPD are infected with Pneumocystis. Because infection with Pneumocystis is treatable with antibiotics, we might be able to offer an effective therapy that could potentially prevent or slow the progression of COPD.